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Biomedical subjects

B R Brown

Publications and source records attributed to B R Brown.

At least 73 records · Page 4Linked to original sources
PubMed1980

Mutagenesis by photoaffinity labeling using selected azidofluorenes.

Several 2-azidofluorenes have been synthesized for use as photoaffinity labels inside bacteria. In the dark they were not mutagenic for any Salmonella typhimurium tested. When photolyzed inside the bacteria, all were mutagenic for strain TA1538 to varying degrees, and were considerably less mutagenic in the corresponding repair positive TA1978. None were mutagenic for strain TA1535 or TA1537, although most compounds were toxic for those strains when photolyzed.

Affinity Labels↗
PubMed1980

Acridine structure correlated with mutagenic activity in Salmonella.

The structural basis for direct mutagenicity of acridines was studied by testing 50 different analogs in the Ames Salmonella tester strains without the addition of mammalian activating enzymes. These experiments showed that the single most effective substituent for frameshift mutagenesis in strain TA1537 is an amino group at the "9" position, while an amino group at either the "3" or "1" position is less effective. Other substitutions at the "9" position demonstrate decreased frameshifting activity compared to 9-aminoacridine. Furthermore, all substituents in combination with the amino group of 9-aminoacridine also decrease frameshifting activity, except for the addition of another amino group at the "1" position or a methyl at the ring nitrogen. Nitro substituents at the "1" and "3" positions enhance 9-aminoacridine toxocity. All nitro substituents decrease typical acridine-frameshift mutagenesis for strain TA1537, but they induce mutagenic activity either in the other type of frameshift strain, TA1538, or in the base-pair substitution strain TA1535. These studies have provided important structure-function relationships for acridine mutagenicity and toxicity in Salmonella. Consequently, this biological system has provided a sensitive means for determining the structural requirements for mutagenic mechanisms.

Acridines↗
PubMed1980

Anesthesia for pheochromocytoma.

Anesthetic management of pheochromocytoma should be based on very reliable pharmacologic principles. The aura and mystique surrounding management of this endocrinopathy is not justified. Patient care for this problem is strengthened by increased knowledge of the pathophysiology involved, and anesthesia is rather straightforward and intellectually satisfying.

Adrenal Gland Neoplasms↗
PubMed1980

Comparison of the biotransformation and hepatotoxicity of halothane and deuterated halothane.

To investigate the effect of deuterium substitution on the biotransformation and hepatotoxicity of halothane, male, phenobarbital-pretreated rats were exposed for 2 hr to 1% halothane or deuterated halothane (d-halothane) delivered in 14% O2-85% N2. The exposures were performed at mildly hypoxic conditions (14% O2) since it was previously established that the decreased oxygen tension promotes both the reductive metabolism of halothane and halothane-induced liver injury. At the end of anesthesia or at 24 hr, the rats were sarificed so that blood, liver and urine samples could be obtained for measurement of metabolites and assessment of liver damage. Deuterium substitution did not affect the levels of reductive metabolites of halothane (fluoride, CF3CH2Cl and CF2CHCl) nor did it alter the degree of hepatotoxicity as assessed by serum glutamic-pyruvic transaminase levels and morphological examination. The levels of oxidative metabolites (CF3COOH and bromide) were significantly reduced at the end of anesthesia and at 24 hr. It is concluded that halothane-induced hepatotoxicity is initiated by reactive intermediates formed during its reductive metabolism and that cleavage of the C-H bond is not involved in this pathway. The oxidative biotransformation of halothane proceeds by an oxygen insertion reaction at the C-H bond. Thus, the increased stability of the C-D bond explains the reduction in oxidative metabolities observed after exposure to d-halothane.

Animals↗
PubMed1979

Quantitative analysis of volatile halothane metabolites in biological tissues by gas chromatography.

A simple and sensitive gas chromatographic method for the determination of 2-chloro-1, 1-difluoroethylene (CDE) and 2-chloro-1,1,1-trifluoroethane (CTE), two highly volatile metabolites of halothane, in blood, liver and isolated hepatic microsomes is described. The entire head-space in equilibrium with a known volume or weight of the sample is injected into the gas chromatograph equipped with a flame ionization detector. Quantification is accomplished with standards prepared by fortifying blank samples with known concentrations of CDE and CTE which are treated under the same conditions as the samples. Detection limits for CDE and CTE were 2 pmole/ml in blood and 10 pmole/g in liver and the mean relative standard deviations are no greater than +/- 6% except for CTE in hepatic microsomes (+/- 9%). A preliminary study of blood CDE and CTE levels in humans anesthetized with halothane is reported.

Chromatography, Gas↗
PubMed1979

Ethidium bromide enhancement of frameshift mutagenesis caused by photoactivatable ethidium analogs.

Ethidium azide analogs (3-amino-8-azido-ethidium monoazide and ethidium diazide) have been developed as photosensitive probes in order to analyze directly the reversible in vivo interactions of ethidium bromide. Our preliminary observations [11], relating the mutagenic potential of the monoazide analog of ethidium, have been extended and refined, using the highly purified ethidium azide analogs [5]. A number of physical-chemical studies indicate that the monoazide analog interaction with nucleic acids, prior to photolysis, resembles remarkably the interaction of the parent ethidium (unpublished). It was anticipated, therefore, that competition by ethidium for the ethidium monoazide mutagenic sites in Salmonella TA1538 would be observed when these drugs were used in combination. Previous results in fact showed a decreased production of frameshift mutants when ethidium bromide was added to the ethidium monoazide in the Ames assay [1]. However, more extensive investigations, reported here, have shown that this apparent competition was the result of neglecting the toxic effects of ethidium monoazide and its enhanced toxocity in the presence of ethidium bromide. Conversely, an enhancement of the azide mutagenesis and toxicity for both the mono- and diazide analogs was seen when ethidium bromide was used in combination with these analogs.

Azides↗
PubMed1979

An animal model of halothane hepatotoxicity: roles of enzyme induction and hypoxia.

Exposure of phenobarbital-pretreated male Sprague-Dawley rats to halothane, 1 per cent, for two hours under conditions of hypoxia (FIO2 0.14) resulted in extensive centrilobular necrosis within 24 hours. Accompanying the morphologic damage were an increase in serum glutamic pyruvic transminase (SGPT) and a decrease in hepatic microsomal cytochrmoe P-450. Glutathione levels in the liver were unchanged. Phenobarbital-pretreated rats anesthetized with halothane, 1 per cent, at FIO2 0.21 had only minor morphologic changes at 24 hours. Hepatic injury was not apparent in any non-phenobarbital-induced rat or in any induced animal exposed to ether at FIO2 0.10 or to halothane at FIO2 0.99. There was a 2.6-fold increase in the 24-hour urinary excretion of fluoride in those rats in which extensive centrilobular necrosis developed. The in-vivo covalent binding to lipids of 14C from 14C-halothane also was increased markedly when 14C-halothane was administered intraperitoneally to phenobarbital-induced rats maintained hypoxic (FIO2 0.14) for two hours. These results support the authors' hypothesis that halothane is metabolized to hepatotoxic intermediates by a reductive or non-oxygen-dependent cytochrome P-450-dependent pathway. This animal model of halothane-induced hepatotoxicity may be clinically relevant. A decrease in hepatic blood flow during halothane anesthesia may decrease the PO2 available to hepatocytes and thus direct the metabolism of halothane along its reductive, hepatotoxic pathway.

Alanine Transaminase↗
PubMed1978

Cyclobenzaprine in intractable pain syndromes with muscle spasm.

The effectiveness of cyclobenzaprine hydrochloride, a new tricyclic skeletal muscle relaxant, was shown in patients with long-term intractable pain of cervical and lumbar origin aggravated by skeletal muscle spasm and tenderness. The investigation was double-blind and randomized, comparing cyclobenzaprine hydrochloride (10 mg three times a day) with diazepam (5 mg three times a day) and with placebo. After two weeks of treatment, the 16 patients in the cyclobenzaprine group showed an overall improvement in pain variables as did the 16 patients in the diazepam group. No serious adverse reactions to cyclobenzaprine were observed in the study. However, dry mouth due to cyclobenzaprine's anticholinergic action and mild degrees of drowsiness were encountered more often than with diazepam or placebo.

Adult↗